Hepatitis B is an infectious inflammatory illness of the liver caused by HBV. The disease has caused epidemics in parts of Asia and Africa, and hepatitis B is highly endemic in China. About a third of the world population has been infected with HBV at one point in their lives, and approximately 300 million people worldwide are chronically infected with HBV. Hepatitis B is a major global health problem and the most serious type of viral hepatitis as it puts people at high risk of death from cirrhosis of the liver and hepatocellular carcinoma.
A vaccine against hepatitis B has been available since 1982. The hepatitis B vaccine, which is made from inactivated HBV, is about 95% effective in preventing infection and its chronic consequences. Once infected with HBV, however, there are only two types of agents approved to treat a chronic HBV infection. Pegylated interferons are effective in only a small fraction of patients, have serious side effects, and are expensive. Nucleoside or nucleotide analogues are potent inhibitors of HBV DNA replication, but they fail to clear the covalently closed circular (ccc) DNA, the template of viral DNA replication and protein expression. They also fail to block the expression of viral proteins. For example, hepatitis B surface antigen (HBsAg) is believed to promote viral persistent infection by inducing immune tolerance. Nucleoside analogue therapy rarely promotes the loss of HBsAg followed by the rise of corresponding antibody (called HBsAg seroconversion), a marker of sustained virological response. In this regard, targeting host factors for HBV entry may block the viral lifecycle at the first step. Targeting HBsAg secretion may also promote HBsAg seroconversion.
Chronic infection with HBV greatly increases the risk to develop liver cancer. Current therapies with interferons and nucleoside or nucleotide analogues suffer from low response rate or induction of drug resistance. Maintenance of a persistent infection in the liver requires continuous release of infectious virions from infected hepatocytes for de novo infection of regenerated cells.
Despite decades of extensive search, host factors required for HBV entry into hepatocytes remain ill defined. At present, heparan sulfate proteoglycan (HSPG) has been identified as a low-affinity HBV receptor. A high-affinity, proteineous HBV receptor remains obscure, although a sodium-dependent, co-transporting polypeptide (NTCP) has recently been proposed as a HBV receptor (Yang H et al., eLife 1: e00049). HBV expresses three envelope proteins: large (L), middle (M), and small (S). These three proteins are translated from the same gene through alternative, in-frame start codons, with the M protein comprising extra N-terminal sequence (preS2 domain) over the S protein, and the L protein comprising extra N-terminal sequence (preS1 domain) over the M protein. The envelope proteins, especially the L protein, are believed to mediate HBV attachment to the high-affinity HBV receptor. Many proteins have been identified that bind to a HBV envelope protein, but none of them are receptors for HBV on hepatocytes.